Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 22; pp. 6538 - 6541
• Main Authors: Yang, Zhicai, Fairfax, David J., Maeng, Jun-Ho, Masih, Liaqat, Usyatinsky, Alexander, Hassler, Carla, Isaacson, Soshanna, Fitzpatrick, Kevin, DeOrazio, Russell J., Chen, Jianqing, Harding, James P., Isherwood, Matthew, Dobritsa, Svetlana, Christensen, Kevin L., Wierschke, Jonathan D., Bliss, Brian I., Peterson, Lisa H., Beer, Cathy M., Cioffi, Christopher, Lynch, Michael, Rennells, W. Martin, Richards, Justin J., Rust, Timothy, Khmelnitsky, Yuri L., Cohen, Marlene L., Manning, David D.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.11.2010; Elsevier
• Subjects: 5-HT3 receptor antagonist; Alosetron; Benzoxazole; Benzoxazoles - chemistry; Benzoxazoles - pharmacology; Biological and medical sciences; Diarrhea; Digestive system; Drug Discovery; IBS; Irritable bowel syndrome; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Ramosetron; Receptors, Serotonin, 5-HT3 - drug effects; Serotonin Antagonists - chemistry; Serotonin Antagonists - pharmacology; Serotoninergic system; Alosetron; Irritable bowel syndrome; Benzoxazole; Diarrhea; IBS; Ramosetron; 5-HT3 receptor antagonist; Quinuclidine derivatives; Nitrogen heterocycle; Structure activity relation; Chlorine Organic compounds; Bicyclic compound; Aromatic compound; Antagonist; Chemical synthesis; Oxygen nitrogen heterocycle; Rodentia; Oral administration; Antidiarrheal agent; In vitro; Vertebrata; Metabolic stability; Mammalia; Mouse; Animal; 5-HT3 Serotonine receptor; Affinity; Carboxamide; 5-HT; receptor antagonist; Duration of action
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.09.038

The discovery of a novel series of benzoxazole-4-carboxamides is described. A structure–activity relationship study resulted in the identification of 2-amino benzoxazoles 41 and 48 as selective, orally bioavailable 5-HT3 receptor antagonists. A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT3 receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT3A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT3 receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT3 receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).